A major pathological feature of Alzheimer's Disease (AD) is neuroinflammation, which has been characterized as both a cause and a consequence of chronic oxidative stress. Oxidative stress and inflammatory reactions are combatted by different antioxidant and redox-regulating factors. One such factor is the thiol-dependent peroxidase, Peroxiredoxin 6 (Prx6), which is known to possess antioxidant function through its peroxidase activity (PRX) and to regulate inflammation through its phospholipase activity (PLA). It is expressed at high levels in Alzheimer's patients and, when overexpressed in a mouse AD model, actually exacerbates the AD phenotype. We propose to use the Drosophila model to test the hypothesis that it is the phospholipase activity in the Prx6 gene that elicits a chronic state of inflammation and contributes to the Alzheimer's phenotype. In Drosophila, there exist two Prx6 variants, one of which (dPrx2540) is equivalent to the bifunctional mammalian form while the other (dPrx6005) does not possess PLA activity. The objectives of this proposal are two-fold. In Aim 1 both the bifunctional variant dPrx2540 as well as the variant possessing only peroxidase activity (dPrx6005) will be overexpressed in brain tissue to determine their relative impact in AD and control backgrounds, using a battery of tests, including survivorship, neuronal pathology and physical activity. In Aim 2, dPrx6 isoform transgenes will be engineered in which either the peroxidase activity or the phospholipase activity or both are ablated and these will be used to generate transgenic lines. We will then be in a position to determine the differential roles of PLA and PRX activities of the bifunctional dPrx2540 on AD progression. This will be achieved by transgene expression targeted specifically to neuronal tissue in both AD and normal backgrounds. A positive outcome in this endeavor would point to a series of potential targets for translational research, ranging from phospholipase activity to arachidonic acid and other downstream effectors of inflammation.